Original Article
Long-Term Outcome after Surgical Repair of Isolated Atrial Septal Defect — Follow-up at 27 to 32 Years
N Engl J Med 1990; 323:1645-1650December 13, 1990
- Abstract
- Abstract
Background.
Atrial septal defects have been surgically correctable for more than 30 years. The long-term survival rates among patients treated in the early era of cardiac surgery are poorly documented, but such data are of critical importance to the future medical care, employability, and insurability of these patients.
Methods.
To determine the natural history of surgically corrected atrial septal defects, we studied all 123 patients who underwent repair of an isolated defect (ostium secundum or sinus venosus) at the Mayo Clinic between 1956 and 1960, 27 to 32 years after the procedure. The follow-up status of all patients was determined by written questionnaires and telephone interviews. Hospital records and death certificates were obtained if interim hospitalization or death had occurred.
Results.
The overall 30-year actuarial survival rate among survivors of the perioperative period was 74 percent, as compared with 85 percent among controls matched for age and sex. The perioperative mortality was 3.3 percent (four deaths). Actuarial 27-year survival rates among patients in the younger two quartiles according to age at operation (≤11 years and 12 to 24 years) were no different from rates among controls — 97 percent and 93 percent, respectively. In the two older quartiles (25 to 41 years and >41 years), 27-year survival rates were significantly less (P<0.001) — 84 percent and 40 percent, respectively — than in controls (91 and 59 percent). Independent predictors of long-term survival according to multivariate analysis were age at operation (P<0.0001) and systolic pressure in the main pulmonary artery before operation (P<0.0027). When repair was performed in older patients, late cardiac failure, stroke, and atrial fibrillation were significantly more frequent.
Conclusions.
Among patients with surgically repaired atrial septal defects, those operated on before the age of 25 have an excellent prognosis, but older patients require careful, regular supervision. (N Engl J Med 1990; 323: 1645–50.)
Article Activity
- Article
ISOLATED atrial septal defect is the third most common form of congenital heart disorder presenting after childhood (bicuspid aortic valve and mitral-valve prolapse are first and second).1 2 3 Even if unrepaired, this defect is often compatible with prolonged survival into adulthood.4 5 6 Studies of patients with an unrepaired secundum atrial septal defect indicate that their average age at death was 39 to 49 years.7 Results of medium-term follow-up study after surgical correction of atrial septal defects are well documented, but information on long-term survival (postoperative survival lasting 25 to 30 years) and sequelae such as arrhythmias, cardiac failure, and stroke is scanty.8 9 10 11 It is unknown whether patients have a normal life expectancy after successful closure of their defect. It has been postulated that early repair of atrial septal defect, before the development of increased pulmonary-artery pressure, is associated with excellent long-term survival, but whether such survival is similar to that of an age- and sex-matched control population is a matter of speculation. Such information is critically important with regard to the future employability and insurability of the increasing number of long-term survivors of repair of atrial septal defects.
We present the results of postoperative follow-up of 27 to 32 years (or until death) after the closure of an atrial septal defect in the first 123 consecutive patients who underwent this operation at the Mayo Clinic between 1956 and 1960, giving particular attention to the influences on the long-term results of age at operation, the preoperative systolic pressure of the main pulmonary artery, the additional repair of partial anomalous pulmonary venous drainage, and the duration of cardiopulmonary bypass.
Methods
Patients and Definitions
All patients who underwent surgical repair of an isolated atrial septal defect with heart—lung bypass at the Mayo Clinic between 1956 and 1960 were included in this study. This period was selected to allow a minimal length of follow-up of 27 years (or follow-up until death); the maximal length of follow-up was 32 years. Patients with either an ostium secundum or a sinus venosus atrial septal defect were included. Excluded from the study were patients with other hemodynamically severe congenital heart disorders, including pulmonary-valve stenosis, infundibular stenosis, primum atrial septal defect (partial atrioventricular canal), and common atrium. Also excluded were 7 patients initially referred for reoperation for closure of atrial septal defect and 18 foreign patients, as well as patients whose defect had been repaired by the atrial-well technique (which is no longer used and is of only historical importance). All patients with additional repair of partial anomalous pulmonary venous drainage were included in the study.
The follow-up status of the patients was determined largely by written questionnaire. Failure to respond elicited a second questionnaire, followed by a telephone interview with the patient or a first-degree relative if the patient was unavailable or dead. If death, hospitalization, or a cardiovascular event had occurred, either the death certificate or the records of the hospital or physician were reviewed for follow-up data.
A cardiovascular event was defined as any of the following: congestive heart failure, infective endocarditis, pericarditis, stroke or a transient ischemic attack, arterial thromboembolism, myocardial infarction, complete heart block or sinus-node disease requiring pacemaker implantation, valvular heart surgery, or reoperation for atrial septal defect. Only events occurring in hospitalized survivors of the event were analyzed.
To assess the occurrence of late tachyarrhythmias, the patients or their current physicians were questioned about documented arrhythmias and any use of antiarrhythmic medications. In particular, atrial fibrillation or flutter, whether sustained or paroxysmal, that occurred at any time at least 30 days after operation was defined as late fibrillation or flutter.
Statistical Analysis
Differences in continuous variables between age groups were examined by analysis of variance. The probability of survival was estimated according to the Kaplan–Meier method.12 Survival curves were compared by means of the log-rank test.13 The association of continuous variables with survival and the association of combinations of variables with survival were estimated with the Cox proportional-hazards model.14 The variables for which values were statistically significant (P<0.05) or close to significance according to univariate analysis were then evaluated in multivariate analyses.
Results
The study group consisted of 123 consecutive patients, 76 female (62 percent) and 47 male (38 percent). The mean (±SD) age at operation was 26±17 years (range, 2 to 62 years; median, 24).
The patients were divided into quartiles according to their age at operation: ≤11 years old, 33 patients: 12 to 24 years old, 29; 25 to 41 years old, 32; and >41 years old, 29. The patients were also categorized according to the presence or absence of moderate-to-severe pulmonary hypertension (main-pulmonary-artery systolic pressure ≥40 mm Hg) at the time of preoperative cardiac catheterization.
Preoperative Period
Clinical Features*
Ninety-two patients (75 percent) were symptomatic at the time of operation, the most common symptoms being dyspnea on exertion, fatigue, palpitations, and syncope. Among the four age quartiles, there were no significant differences in the presence or the degree of preoperative dyspnea. The preoperative use of digoxin differed significantly among the age quartiles: 12 percent of the patients ≤11 years old at operation were taking the drug, as were 7 percent of those 12 to 24 years old, 38 percent of those 25 to 41 years old, and 76 percent of those >41 years old (P<0.001). The preoperative use of diuretic agents also differed significantly among the quartiles: none of the patients ≤11 years old or 12 to 24 years old at operation were taking the drug, whereas 13 percent of those 25 to 41 years old and 48 percent of those >41 years old were taking it (P<0.001). The preoperative use of quinidine and a history of palpitations also were more frequent in the older quartiles.
Hemodynamic Function
Hemodynamic data were available for 101 patients (82 percent). The systolic pressure of the main pulmonary artery was significantly higher in the oldest quartile (>41 years) (Fig. 1Figure 1
Systolic Pressure of Main Pulmonary Artery before Closure of Atrial Septal Defect, According to Age at Operation (P = 0.0034 by Analysis of Variance).), but there were no significant differences between the quartiles in the size of the shunt or the ratio of pulmonary to systemic flow. Since values for pulmonary vascular resistance were available for only 52 patients (42 percent), this variable was not entered into the analysis performed with the Cox proportional-hazards model. No patient had a measurable right-to-left shunt.*See NAPS document no. 04825 for one page of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York. NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada add postage of $4.50 ($1.50 for microfiche postage). There is an invoicing charge of $15 on orders not prepaid. This charge includes purchase order.
Surgical Technique*
There was no significant difference among the age groups in the use or the type of intraoperative patch, repair of partial anomalous pulmonary venous drainage, or type of atrial septal defect (ostium secundum or sinus venosus). The atrial septal defect was repaired during cardiopulmonary bypass in all patients; in addition, hypothermia was induced in 25 patients. The repair of partial anomalous venous drainage and tricuspid annuloplasty were carried out in 24 and 2 patients, respectively.
Late Postoperative Period
Overall Survival
The perioperative mortality was 3.3 percent (four deaths); three patients died of postoperative heart failure, and one could not be weaned from cardiac bypass. All four were between 46 and 50 years old, and all had pulmonary hypertension. The mean (±SD) duration of follow-up in the survivors was 27.2±2.0 years (median, 27.1; maximum, 31.4). Only 1 of the 120 patients who survived repair was lost to follow-up. Kaplan–Meier estimates of survival in the 119 patients included in the survival analysis were 97 percent 5 years after operation, 90 percent at 10 years, 88 percent at 15 years, 83 percent at 20 years, 81 percent at 25 years, and 74 percent at 30 years, as compared with 99, 98, 96, 94, 90, and 85 percent, respectively, in an age- and sex-matched control population (from the West North Central region of the United States, 1980 [Bureau of Vital Statistics, Department of Health, Education, and Welfare]).
Survival According to Age at Operation
Survival in the two younger quartiles was not statistically different from that in the comparable control groups (Fig. 2Figure 2
Long-Term Survival of Patients Surviving the Perioperative Period, According to Age at Operation.). Long-term survival was 84 percent in the third quartile at 27 years, as compared with 91 percent in the control population. Actuarial survival was 40 percent in the oldest quartile at 27 years, approximately two thirds of the proportion surviving in the control group — 59 percent. The excess mortality occurred early and continued throughout the follow-up period.Figure 3Figure 3
Long-Term Survival of Patients Surviving the Perioperative Period, According to Age at Operation and Main-Pulmonary-Artery Systolic Pressure before Operation. shows the effect of increased systolic pressure of the main pulmonary artery before operation on long-term survival. Survival in patients 24 years of age or younger at operation who had normal or slightly increased pulmonary-artery pressure (<40 mm Hg) was no different from survival in a control population. The presence of moderate or severe pulmonary hypertension (≥40 mm Hg) had a markedly adverse effect on survival in patients more than 24 years old at the time of operation.Age at operation and preoperative main-pulmonary-artery systolic pressure were significant predictors of long-term survival according to univariate analysis, as were six other variables (Table 1Table 1
Significant Predictors of Long-Term Survival in Patients Undergoing Repair of Atrial Septal Defects, According to Univariate and Multivariate Analyses.); both these variables were also significant according to multivariate analysis.Late Mortality*
There were 27 late deaths; the reported cause of death was determined in all patients but 1, who had died abroad. The cause of death was determined from death certificates in 21 cases, review of hospital records in 4 cases, and direct contact with a physician in 1 case. Autopsies were performed in 4 cases. There were 18 reported cardiovascular deaths (the cause of death according to the death certificate was heart failure in 5 patients, congenital heart disease in 3, valvular heart disease in 2, myocardial infarction in 1, unspecified cardiac disease in 2, and stroke in 5). Two apparently healthy young men (31 and 32 years old) died in single-vehicle accidents when they suddenly lost control of their vehicles. In 1 man an autopsy determined the cause of death to be asphyxia due to compression of the chest and neck; no secondary cause of death was found. The possibility that the causes of these 2 deaths were primarily arrhythmogenic cannot be excluded. There were 6 noncardiac deaths (due to carcinoma in 3 patients, sepsis in 2, and respiratory failure in 1). In 1 patient whose death was reported as noncardiac, heart failure was listed as a contributory factor. Thus, cardiac death, which occurred in 13 patients (48 percent), and death due to stroke, in 5 patients (19 percent), accounted for the majority of reported causes of late deaths. All patients for whom stroke was listed as the cause of death had been in atrial fibrillation during follow-up.
Late Cardiac Events
Late fatal and nonfatal cardiovascular events (occurring between 30 days after operation and November 1987) are shown in Table 2Table 2
Summary of Late Cardiac Events According to Age at Operation.. It is noteworthy that late cardiac events occurred in 57 percent of the patients who were more than 24 years old at operation, but in only 15 percent of those 24 years old or younger at operation (Table 2). These groups are not directly comparable because of the expected increase in cardiac events among the older patients, but the relatively low incidence of these events among patients undergoing operation at a young age is noteworthy.Atrial Fibrillation and Flutter
The incidences of preoperative and late atrial fibrillation or flutter are shown in Figure 4Figure 4
Incidences of Preoperative and Late Atrial Fibrillation or Flutter, According to Age at Operation. (such late events were defined as occurring more than 30 days after operation). We did not distinguish between paroxysmal and sustained arrhythmias. Both preoperative and late atrial fibrillation or flutter became more common as the age at operation increased. Although these groups are not directly comparable because of the expected increase in atrial fibrillation or flutter among older patients, a trend is evident.Nineteen of the 123 patients were in atrial fibrillation or flutter before repair of their atrial septal defect, and 13 of these 19 (68 percent) were still in atrial fibrillation or flutter at the time of late follow-up. Of the 104 patients in sinus rhythm before operation, 80 (77 percent) remained in sinus rhythm during long-term follow-up.
Discussion
The series of patients studied was intentionally limited to those in whom follow-up could be determined for a period of at least 27 years or the period up to death. The excellent overall survival confirms the long-term efficacy of surgical treatment for both ostium secundum and sinus venosus atrial septal defects, with or without repair of an associated partial anomalous pulmonary venous drainage. Among the survivors of the operation, subsequent survival overall was good but less than that in an age- and sex-matched control population. Nevertheless, subsequent survival was significantly better than survival among medically treated historical controls.15 16 17 18 19 20 21 22 23 24
In survivors of the perioperative period, closure of an atrial septal defect at or before the age of 24 years was associated with long-term survival not significantly different from that in an age- and sex-matched control population. Closure at the ages of 25 to 41 years was associated with long-term survival that was good but shorter than expected. Closure after 41 years of age was associated with significantly increased late mortality. The decrease in long-term survival when closure was performed at the age of 25 or later is not explicable on the basis of higher right ventricular or pulmonary-artery pressure alone. Although the frequency of pulmonary hypertension is considered to increase with age,25 our results indicate that age at operation is the most powerful independent predictor of long-term survival. Our data suggest that age and pulmonary-artery pressure have an incremental effect on long-term survival. Values for pulmonary vascular resistance were available for only 52 of our patients (42 percent), and this variable was not included in our statistical analysis.
St. John Sutton et al.5 reported the beneficial effect of closure of an atrial septal defect in a series of patients 60 years old or older. It is probable that patients who survive to this age without correction of their defect represent a highly selected population by virtue of their long survival. We do not imply that being older is a contraindication to repair of an atrial septal defect, but the long-term results of repair at older ages are unfavorable as compared with those of correction at earlier ages.
The explanations for the power of age at operation as a predictor of late mortality are speculative and probably multifactorial. long-standing volume and pressure overloads, pulmonary vascular disease, and perhaps atrial fibrillation as a result of atrial dilatation could contribute. On analysis of right ventricular biopsy specimens from patients undergoing operation for congenital heart lesions associated with increased right ventricular pressures, Jones and Ferrans26 found that interstitial fibrosis, myofibrillar lysis, Z bands, and other histologic abnormalities increased progressively with age and were universally present by the age of 30 years or later. These morphologic changes would be consistent with an adverse effect on cardiac reserve and myocardial contractility.10 , 27 When an atrial septal defect is present, the left ventricle may eventually fail.28 Several mechanisms have been proposed, including "under-utilization" of the left ventricle,29 , 30 interaction between the overloaded right ventricle and diastolic compliance of the left ventricle,31 abnormal interventricular septal motion,32 and intrinsic impairment of left ventricular contractility.33 , 34 Whether the development of late heart failure occurs primarily on the left or right side cannot be determined from our data. The perioperative mortality in our study (3.3 percent) is exceptionally high according to today's standards but is similar to rates for repair of atrial septal defect at other institutions.
During part of this study, the use of the atrial-well technique to repair atrial septal defects overlapped with the use of cardiopulmonary bypass in this operation. The criteria used to select patients for either procedure at that time cannot be assessed now, but it is certainly possible that the patients who underwent cardiopulmonary bypass were at higher risk than those treated by the atrial-well technique, since cardiopulmonary bypass was probably safer. Nonetheless, our basic conclusions are unaltered in that even in a population that may have been biased toward patients at "higher risk," those who were operated on at a younger age had excellent survival.
Compressed Ivalon sponge (described in Table 1) was used in patch closure for atrial septal defects during the early years of heart surgery. Ivalon is now known to be unsuitable for this purpose because the patch tended to undergo late central lysis and hence allow reestablishment of the septal defect.35 A high incidence of recurrent septal defect would be expected to influence the late result of operation markedly; this supposition is supported by the present study, in which the outcome was far worse in the 13 patients in whom Ivalon was used. Today, atrial septal defects are closed by means of direct suture or an autologous pericardial patch. Synthetic materials, including Teflon (tetrafluoroethylene), are used less frequently.
Retrospective determination of the cause of death by means of death certificates and hospital records has limitations but nevertheless does provide useful information. In four patients, a noncardiac cause of death was obvious. For 20 patients the death certificate listed a cardiovascular cause, and in the 2 patients who died in vehicular accidents a primary arrhythmogenic cause could not be excluded. However, among the patients who were operated on before they were 17 years old, there were no deaths that could be attributed to a cardiovascular cause.
Our data confirm that the presence or absence of atrial fibrillation or flutter before operation may be a major determinant of the maintenance of sinus rhythm after operation, and the prevalence of preoperative atrial fibrillation or flutter increases progressively from younger to older groups.36 We may have substantially underestimated the occurrence of atrial fibrillation or flutter, and considerably more patients may have had undetected episodes of atrial arrhythmia. The principal importance of atrial fibrillation or flutter lies in its association with stroke. Twenty-two percent of late deaths in our patients were due to stroke; all these deaths occurred in patients with atrial fibrillation or flutter. Our data suggest that early closure of atrial septal defects may protect against the late development of atrial fibrillation.
With the increase in survival after surgical correction of congenital heart defects into adulthood, it has become important to identify the subgroups of patients who can be expected to have long-term sequelae and those who may have normal survival. Our data suggest that in patients who are less than 25 years of age at the time of closure of an atrial septal defect and who do not have moderate or severe pulmonary hypertension, long-term survival is not significantly different from that in age- and sex-matched controls. From the perspective of employment and insurability, such patients should be strongly reassured.
The approach to older patients should be different. In view of the increased risk of unfavorable cardiovascular events, vigilance is advisable, along with careful, regular surveillance. These patients seem to be at increased risk for atrial fibrillation, embolic stroke, or heart failure. All patients, irrespective of their age at operation, should be monitored for the development of late atrial arrhythmias.
We are indebted to Kim D.Jones and Chu-Pin Chu (Department of Health Sciences Research) for their invaluable help.
Source Information
From the Division of Cardiovascular Diseases and Internal Medicine (J.G.M., B.J.G., M.D.M.), the Section of Pediatric Cardiology (D.D.M., C.J.P.), the Section of Biostatistics (D.M.I.), and the Division of Thoracic and Cardiovascular Surgery (D.C.M., F.J.P., G.K.D.), Mayo Clinic and Mayo Foundation, Rochester, Minn.; and the Department of Surgery, University of Alabama Medical Center, Birmingham (J.W.K.). Address reprint requests to Dr. Gersh at the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
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